WO2002015889A1

WO2002015889A1 - Transdermal therapeutic system for treating restless-legs-syndrome

Info

Publication number: WO2002015889A1
Application number: PCT/EP2001/009823
Authority: WO
Inventors: Reinhard Horowski; Johannes Tack; Adalbert Engfer
Original assignee: Neurobiotec Gmbh
Priority date: 2000-08-24
Filing date: 2001-08-24
Publication date: 2002-02-28
Also published as: DK1311249T3; EP1311249B1; AU2002210463B2; PT1311248E; EP1311249A1; DK1311248T3; ATE361062T1; DE10066158B4; US20040101550A1; JP2004530631A; DE10043321B4; AU1046202A; ES2286146T3; DE50112452D1; DE50115161D1; DE10043321A1; US20040028723A1; JP2004506682A; ATE444742T1; EP1311248B1

Abstract

The invention relates to the use of a transdermal therapeutic system (TTS) comprising a medicinal layer, which contains at least one matrix comprising an active ingredient and /or an active ingredient reservoir and a diffusion barrier situated on the skin side of the active ingredient reservoir and permeable to active ingredients, in addition to, an ergoline-derivative or physiologically compatible salt with an acid thereof, as an active ingredient, for producing a means for treating the restless-legs-syndrome.

Description

Transdermal therapeutic system for the treatment of restless legs syndrome

description

The invention relates to the use of a transdermal therapeutic system (TTS) comprising a medicament layer which contains at least one matrix containing an active substance and / or an active substance reservoir and an active substance-permeable diffusion barrier on the skin side of the active substance reservoir as well as an ergoline derivative or its salt as active substance a medicine to treat restless legs syndrome.

Restless Legs Syndro (RLS) is a neurological disorder that occurs in all age groups, but more often in older age, and the symptoms of which mainly manifest themselves in the fact that cramps and leg pain occur as a result of dysesthesia and paraesthesia Trigger urge to move. Since these symptoms usually become noticeable at night or during periods of reduced activity such as sitting and resting, the urge to move leads to restlessness during the day and sleep disorders at night. This significantly affects the quality of life of those affected.

Treatment of restless legs syndrome with single oral dopa inerger is known

Medications such as Lisurid in the evening lead to an improvement in the symptoms and a general negative impact on the quality of life being affected. In contrast to Parkinson's therapy, in which dopaminergic pharmaceuticals and their combinations are taken throughout the day, the development of a tolerance to the acute (flooding-related) dopaminergic side effects is impaired in the case of a single oral intake for the treatment of restless legs syndrome, ie Known side effects such as orthostasis, hypotension, dizziness, nausea and vomiting may occur with each effective dose. Unpredictable and uncontrollable sleep attacks, as have recently been reported, can also occur. Furthermore, the plasma concentration is not constant, but is subject to large fluctuations, not only for kinetic reasons, but also depending on the individual boundary conditions of the intake (type and time of food intake, etc.). Therefore, there is also the risk of intermittent overdosing, with the result of, for example, REM suppression and the resulting problems and sleep disorders.

In addition, rebound phenomena as well as so-called augmentations, i.e. increased tone, restlessness and urge to move, often.

The invention is based on the technical problem of specifying an agent for the treatment of restless legs syndrome which is free of side effects, but at least shows significantly reduced side effects compared to oral administration, in particular allows the active ingredient to slowly flood in and the amount and duration of which can be controlled well. Here, a transdermal therapeutic system according to the invention described below can also achieve an individually desired controlled duration of action (possibly by removing the plaster). Compared to oral administration, the TTS increases bioavailability, which means that the total dose required to achieve the therapeutically desired effect can be reduced. The α-adrenolytic effect of lisuride and its derivatives has the further advantage in this form of use that nocturnal urge to urinate and other bladder dysfunctions, as is not uncommon in restless leg and Parkinson's patients (also due to the prostate) -Hyperplasia), is significantly improved, which also contributes to the success of the therapy.

The invention relates to the use of a transdermal therapeutic system (TTS) comprising a medicament layer which has at least one matrix containing an active substance and / or an active substance reservoir and an active substance-permeable diffusion barrier on the skin side of the active substance reservoir, and as an active substance an ergoline derivative according to formula I or its physiologically tolerable salt with an acid,

Formula I.

wherein a single bond or a

Is double bond, wherein Rl is an H atom or a halogen atom, in particular a bromine atom, and in which R2 is Cl-4-alkyl, in particular methyl, as an agent for the treatment of restless legs syndrome.

With the invention it is achieved as a particular advantage that - in contrast to the usual oral single dose per day - a continuous active substance flux is set up and thus the plasma concentrations can be set in a defined manner and can be checked with regard to the course. This largely prevents the dopaminergic side effects, such as fatigue, dizziness, vomiting, constipation, which can be observed with single oral doses, because it has been found that these side effects can be avoided if the plasma concentrations of the active ingredient are not subjected to large and rapid fluctuations, such as with oral administration, it adjusts itself automatically, but slowly and continuously. In addition, the problem of oral doses, such as strongly variable absorption rates and less defined Time of the maximum concentration in plasma, for example depending on the type and time of food intake, can be practically eliminated with the invention. In particular, an overdose (and consequently SEM suppression as well as others)

Sleep pattern disorders) is avoided. Furthermore, it can be discontinued comparatively quickly, namely simply by removing the TTS. In contrast to the discontinuation of an orally administered active substance, the breakdown in the plasma takes place quickly and in a controlled manner, as a result of which "hang over", rebound or augmentations can also be avoided. Finally, an individual dosage is easily possible by selecting the Flux F and / or the effective area. F and effective area are preferably selected such that a dose in the range from 10 μg to 2 mg of active ingredient, preferably 50 to 200 μg (for example lisuride), is established per day.

It is preferred if the matrix and / or the

Diffusion barrier is selected with the proviso that the transdermal flux F through human skin, measured according to Example 1, is in the range from 0.1 to 2.0 μg / cm ² / h.

Examples of suitable ergoline derivatives are: bromoisuride (3- (2-bromo-9, 10-didehydro-6-methyl-8α-ergolinyl) -1, 1-diethylurea), terguride (3- (6-methyl-8α-ergolinyl) ) -1, 1-diethylurea) and proterguride (3- (6-propyl-8α-ergolinyl) -1, 1-diethylurea). However, it is preferred if the ergoline derivative is lisuride (3- (9, 10-didehydro-β-methyl-δα-ergolinyl) -1, 1-diethylurea) or its physiologically compatible salt with an acid. The production of Lisurid and the others Ergolines suitable according to the invention are described for example in US 3,953,454, EP 056 358 and US 4,379,790. Possible salts of the ergoline derivative are, for example, sulfates, phosphates, maleates, citrates and succinates and, in particular, hydrogen aleate.

The term TTS encompasses percutaneously acting systems, but also transmucosal systems. A TTS is typically of a flat structure and is applied, for example, to the skin. Attachment to the skin can be carried out using an additional adhesive on the skin side (and permeable to the active ingredient). Likewise, the matrix and / or the diffusion barrier itself can be provided with adhesive properties. Finally, a non-adhesive TTS can be brought into contact with the skin by means of further aids, for example adhesive tapes or bandages. A matrix is a substance in which the active ingredient is immobilized. In contrast, the active substance is not necessarily immobilized in an active substance reservoir, which is why the active substance reservoir must be encased. The part of the jacket on the skin side is formed by the diffusion barrier. It goes without saying that the further part of the jacket should be as impermeable as possible, also with regard to diffusion paths, for the active substance. In this context, the term immobilized means that no uncontrolled flow of active ingredients is possible. In particular, diffusion of an active ingredient in a matrix and / or through a diffusion barrier is not only possible, but set up specifically. The diffusion coefficients ultimately determine the flux of the active ingredient from the TTS in a patient's skin. The dose delivered to a patient's skin is therefore, in a first approximation, a linear function of the effective area of the TTS. The effective area is the contact area of areas of the TTS that are open to diffusion for active substances. TTS can be used for both human and veterinary purposes.

A TTS of the structure mentioned at the outset is known in principle from the literature reference WO 92/20339. This particularly describes the effect of propylene glycol lauric acid on the flux, which achieves a considerable increase in flux. The values given relate to solutions applied to skin samples and not to the actual TTS. No information regarding the flux is given for these. In a TTS, significantly lower flux values are achieved compared to values from a solution order.

A TTS containing lisuride is also known from literature reference WO 91/00746. The flux values given therein for human skin samples are not readily transferable to achievable in vivo values.

TTS of the structure described are used for various indications, including Parkinson's. In the case of treatment for Parkinson's disease, the highest possible doses are desirable. A transdermal therapeutic system also improves compliance, which is of great importance for the combination therapies of this disease and its mostly old and multimorbid patients. Better controllability and the possibility of Achieving circadian profiles (e.g. with minimal, as constant as possible stimulation during the night or a break) is particularly cheap here and has not been achieved so far (e.g. to avoid psychosis and improve sleep quality). In the case of the ergoline derivatives lisuride, terguride and bromerguride, their dopamine-partial agonistic or partial antagonistic effect also helps to prevent the development of psychoses or to improve existing psychoses and similar problems.

The TTS can be designed in detail as follows. A cover layer can be arranged on the side of the matrix and / or the active substance reservoir facing away from the skin. This can be formed, for example, with films made of polyethylene or polyester. The thickness is typically 10 to 100 μm. It is possible to pigment and / or metallize the top layer to achieve adequate light protection. Metallization is the application of a very thin layer (typically less than 1 μm, usually in the 10-100 μm range) of a metal, for example aluminum, to the top layer. Pigments can be all pigments commonly used in the coating compositions, including effect pigments, provided that they are physiologically harmless. A removable liner can be provided on the application side, for example a siliconized or fluoropolymer-coated polymeric protective film.

The matrix and / or diffusion barrier can be a substance selected from the group consisting of "polyacrylate, polyurethane, cellulose ether, silicone, polyvinyl compounds, silicate and mixtures thereof Substances and copolymers of these polymer compounds ", preferably polyacrylate, as the main matrix component. A main matrix component forms at least 50% by weight, for example at least 80-90% by weight, of the matrix (the term matrix refers to the finished layer, ie main matrix component (s) with auxiliary substance (s) and active substance (s)) The desired flux is set on the one hand by selecting the substance depending on the diffusion coefficient of the active substance therein and on the other hand and if necessary in coordination with this by selecting the layer thickness of the matrix in the orthogonal direction The thickness range of a matrix is typically in the range from 10 μm to 500 μm.

A preferred polyacrylate adhesive as main matrix component is commercially available under the name GELVA ^® multi polymer solution 7881, available from Monsanto Germany GmbH, Dusseldorf. In this context, express reference is made to the product sold under this name in accordance with the data sheet in the version dated April 23, 1996. Eudragit ^® E100, also available from Röhm, Germany, can also be used well.

With the above polyacrylate adhesives, a particularly advantageous non-trivial combination of properties is obtained, namely optimal flux, good adhesion, good skin tolerance and good durability.

The diffusion barrier can alternatively be a polymer selected from the group consisting of "cellulose esters, cellulose ethers, silicone, polyolefin and mixtures and copolymers of these substances" as Have main barrier component. With regard to the concept of the main barrier component, the above applies analogously to the main matrix component. The diffusion barrier can be designed as a film with a thickness of 10 μm to 300 μm, the thickness of the layer (in conjunction with the diffusion coefficient of the active ingredient in the polymer) being adjusted in accordance with the desired flux.

The matrix and / or the drug reservoir and / or the diffusion barrier can contain auxiliaries customary for TTS. A penetration-enhancing agent, which is preferably selected from the group consisting of "C1-C8 aliphatic, cycloaliphatic and aromatic alcohols, saturated and unsaturated C8-18 fatty alcohols, saturated and unsaturated C8-18 fatty acids, hydrocarbons and hydrocarbon mixtures, is preferably used as auxiliary. Fatty acid esters from C3-19 fatty acids and Cl-6 alkyl monools,

Dicarboxylic acid diesters from C4-8-dicarboxylic acids and Cl-6-alkyl monools, and mixtures of these substances. Penetration enhancing agents improve the flux of the active ingredient through the skin to which the TTS is applied. Examples from the above

Substances are: 1, 2-propanediol, menthol, dexpanthenol, benzyl alcohol, lauryl alcohol, isocetyl alcohol, cetyl alcohol, mineral oil, lauric acid, isopalmitic acid, isostearic acid, oleic acid; Methyl ester, ethyl ester, 2-hydroxyethyl ester, glycerol ester, propyl ester, isopropyl ester, butyl ester, sec. -Butyl ester or isobutyl ester of lauric acid, myristic acid, stearic acid or palmitic acid. The use of dimethyl isosorbide, isopropyl myristate and Lauryl alcohol, most preferred from lauryl alcohol. Crystallization inhibitors, for example, are suitable as further auxiliaries. Crystallization inhibitors include highly disperse silicon dioxide or macromolecular substances such as

Polyvinylpyrrolidones, polyvinyl alcohols, dextrans, dextrans, sterols, bile acids and especially vinylpyrrolidone-vinyl acetate copolymers are suitable, such as Kollidon ^® VA 64.

It is understood that in any case the penetration-enhancing agent must also diffuse sufficiently through the matrix or the diffusion barrier. If a matrix and the auxiliary lauryl alcohol are used, the lauryl alcohol preferably forms 10 to 30% by weight, most preferably 15 to 20% by weight, of the matrix.

The auxiliary substances can in principle form 0 to 50% by weight of the matrix. The active ingredient can form 0.2 to 20% by weight, preferably 1 to 10% by weight, of the matrix. The sum of the shares in

The main matrix component, auxiliary substances and active substances always form 100% by weight.

The dose of the active ingredient in a human body carrying the TTS depends not only on the above diffusion-related properties of the TTS but also on its effective area with the skin. Effective area means the area with which the matrix or the diffusion barrier comes to rest against the skin. The variation preferably takes place in accordance with the desired dose in a range from 1 to 100 cm ² . Within the scope of the invention, in the case of a coordinated flux for a given indication, dose variations which are easy for the patient can be set up by a doctor, namely by choosing a suitable size. The treatment can thus be easily adjusted to different body weights, age groups, etc. In particular, it is possible to equip a TTS, which has a (rather large) standard area, with division markings for partial doses, so that a user can only separate and use a partial section corresponding to a specific dose. Corresponding imprints can easily be attached to the top layer.

Another possible application is the use of a TTS according to the invention for the production of an agent for the treatment or prevention of premenstrual syndrome or its symptoms, F being preferably from 0.1 to 0.5 μg / cm ² / h, and the use for the preparation of an agent for lactation inhibition, where F is preferably from 0.1 to 0.5 μg / cm ² / h.

The invention is explained in more detail below with the aid of examples.

Example 1: Flux measurement

A FRANZ flow diffusion cell is used for the flux measurement. The measuring area is 2 cm ² . 4 cm ² ventral and dorsal skin of a male hairless mouse (MFl hr / hr

Ola / Hsd, available from Harlan Olac, UK), carefully removing subcutaneous fat. A 2 cm ² TTS is applied to the skin used. The acceptor medium is arranged opposite. It is diluted HHBSS (Hepes Hanks Balanced Salt

Solution) containing 5.96 g / 1 Hepes, 0.35 g / 1 NaHC03 and 0.1 ml / 1 lOx HBSS (available from Gibco, Eggenstein, DE). Furthermore, 1000 I.E. / ml penicillin (benzylpenicillin potassium salt, available from Fluka, Neu-Ulm, DE).

The measurement is carried out in detail as follows. The TTS to be measured is first applied to the skin. Immediately afterwards, the skin is mounted in the diffusion cell. The acceptor medium is sampled at intervals of 2 hours between t = 0 and t = 6 hours and 8 hours between t = 6 hours and t = 54 hours. 1 ml of acceptor medium are pumped through the diffusion cell per hour using a peristaltic pump. The temperature of the acceptor medium is controlled by means of a circulating water bath and keeps the surface of the skin at a temperature of 31 ° C with 1 ° C Accuracy.

The drug concentration in the acceptor medium is determined according to the following details using a radioimmunoassay.

Calibration curves: These are constructed using two different methanol solutions of non-radioactive lisuride hydrogen maleate salt, each containing 1 mg / ml. These solutions are different with BSA buffer (0.041 M Na2HPθ2 * 2H2θ,

0.026 M KH2PO4, 0.154 M NaCl, 0.015 M NaN ₃ , 0.1% (w / v)

BSA, pH 7, supplemented with 0.05% (w / v) ascorbic acid) diluted in order to obtain lisuride free base concentrations in the range of 1000-3.9 pg / 0.1 ml. In addition, an active ingredient-free sample (Opg) is used. The calibration samples are analyzed in triplicate. The lisuride concentrations are calculated using the pharmacokinetic RIO PC software, 2.5 (other conventional software can also be used).

Sample preparation: Before the analysis, the acceptor medium is diluted with BSA buffer in order to set concentrations in the evaluable area of the calibration curve. 100 μl of diluted sample are directly subjected to radioimmunological analysis.

Antiserum: The antiseru (rabbit) is obtainable by immunization with the immunogen Lisurid-1 succinyl-BSA. The dilution of the antiserum in the assay is 1: 12500.

Tracer: ³ H-Lisuride hydrogen maleate with a specific activity of 4.3 GBq / mg is used.

Incubation: 0.7 ml BSA buffer with active ingredient, 0.1 ml tracer solution (approx. 5000 cpm / 0.1 ml BSA buffer) and 0.1 ml diluted antiserum (1: 12500) and it is incubated at 4 ° C. for 18 h.

Separation: Antibody-bound lisuride is freed by adding 0.2 ml charcoal suspension (1.25% (w / v) and 0.125% (w / v) dextran in BSA buffer) and incubation for 30 min. separated at 0 ° C. The charcoal is centrifuged at 3000 g for 15 min. sedimented. The supernatant (containing antibody-bound active ingredient) is decanted and sent for radiometric analysis.

Radiometric analysis: 4 ml of the Atomlight (NEN) scintillation cocktail are added to the supernatant. The counting is done with a WALLAC 1409 or 1410 ß scintillation counter without quench control.

Evaluation: The percutaneous skin flux is calculated as follows:

F = (C * R) / (A * T),

where F is the percutaneous flux [ng / cm ² / h], C the active substance concentration in the acceptor medium [ng / ml], R the acceptor medium flow [lml / h], A the measuring area [2cm ² ] and T the sampling time interval [h]. Maximum transdermal drug flux is taken directly from the data. Mean percutaneous flux values are determined during day 1 and day 2 of the experiment based on the cumulatively absorbed dose in the time interval t = 0-22 and t = 22-54.

Information for the production of TTS

Example 2: TTS A

15 mg Kollidon VA 64 (crystallization inhibitor) are dissolved in 15 mg isopropanol. Then 5 mg of lisuride are sprinkled in. 80 mg of polyacrylate adhesive (Gelva 7881) are placed in a beaker and the above suspension is added with rinsing with 30 mg of isopropanol. After thorough mixing, the crystal-free wet mix obtained is extracted with a 500 μm doctor blade on a siliconized liner. Then at 60 ° C for 20 min. dried and finally a top layer was laminated on.

Measurements of the flux according to Example 1 give F a day 1 value of 0.43, a day 2 value of 0.44 and a maximum F of 0.85 (each in μg / cm / h).

Example 3: TTS B

12.5 mg of dimethyl isosorbide are suspended with 2 mg of lisuride in 15 mg of isopropanol. 80 mg of polyacrylate adhesive (Gelva 7881) are placed in a beaker and the above suspension, with rinsing with 30 mg Isopropanol added. After thorough mixing, the crystal-free wet mix obtained is extracted with a 500 μm doctor blade on a siliconized liner. Then at 60 ° C for 20 min. dried and finally a top layer was laminated on.

Measurements of the flux according to Example 1 give F a day 1 value of 0.23, a day 2 value of 0.28 and a maximum F of 0.50 (in each case in μg / cm ² / h).

Example 4: TTS C

27.2 mg Kollidon VA 64 (crystallization inhibitor) and

16.3 mg lauryl alcohol are dissolved at 60 ° C. Then 2 mg of lisuride are dissolved in this solution at 60 ° C. 39.38 mg Eudragit E100, 13.41 mg Citroflex 4A and 1.71 mg succinic acid are melted at 150-200 ° C. After cooling to 80 ° C, the lisuride solution is added with stirring. At 80 ° C, a 500 μm squeegee is drawn out on a siliconized liner. Then it is cooled to 20 ° C. and finally, if necessary, a cover layer is laminated on.

Measurements of the flux according to Example 1 give F a day 1 value of 0.90, a day 2 value of 1.76 and a maximum F of 2.53 (each in μg / cm ² / h).

Claims

claims:

1) Use of a transdermal therapeutic

Systems (TTS) comprising a medicament layer which contains at least one matrix containing an active substance and / or an active substance reservoir and an active substance-permeable diffusion barrier on the skin side of the active substance reservoir, and as active substance an ergoline derivative according to formula I or its physiologically tolerable salt with an acid,

Formula I.

wherein a single bond or a

Is a double bond in which R 1 is an H atom or a halogen atom, in particular a bromine atom, and in which R 2 is Cl-4-alkyl

for the preparation of an agent for the treatment of restless legs syndrome.

2) Use according to claim 1, wherein the matrix and / or the diffusion barrier is selected with the proviso that the transdermal flow F through human skin, measured according to Example 1, is in the range from 0.1 to 2.0 μg / cm ² / h.

3) Use according to claim 1 or 2, wherein the

Ergoline derivative lisuride or its salt with a physiologically acceptable acid.

4) Use according to one of claims 1 to 3, wherein a cover layer is arranged on the side of the matrix and / or the active substance reservoir facing away from the skin.

5) Use according to one of claims 1 to 4, wherein the matrix and / or diffusion barrier is a substance selected from the group consisting of

"Polyacrylate, polyurethane, cellulose ether, silicone, polyvinyl compounds, silicate and mixtures of these substances and copolymers of these polymer compounds", preferably polyacrylate, as the main matrix component.

6) Use according to one of claims 1 to 5, wherein the diffusion barrier is a synthetic polymer selected from the group consisting of

"Cellulose esters, cellulose ethers, silicone, polyolefin and mixtures and copolymers of these substances" as the main barrier component. 7) Use according to any one of claims 1 to 6, wherein the matrix and / or the drug reservoir and / or the diffusion barrier contains a penetration-enhancing agent, which is preferably selected from the group consisting of "C1-C8 aliphatic, cycloaliphatic and aromatic alcohols, saturated and unsaturated C8-18 fatty alcohols, saturated and unsaturated C8-18 fatty acids, hydrocarbons and hydrocarbon mixtures, fatty acid esters from C3-19 fatty acids and Cl-6 alkyl monools, dicarboxylic acid diesters from C4-8 dicarboxylic acids and Cl-6 alkyl monools, and mixtures of these substances.

8) Use of a TTS according to any one of claims 1 to 7 for the preparation of an agent for the treatment or prevention of premenstrual syndrome or its symptoms, wherein F is preferably from 0.1 to 0.5 μg / cm ² / h.

9) Use of a TTS according to one of claims 1 to 7 for the preparation of an agent for

Lactation inhibition, where F is preferably from 0.1 to 0.5 μg / cm ² / h.